bims-nastce 2021-12-12 papers

bims-nastce

Biomed News

on NASH and T cells

Issue of 2021–12–12
eight papers selected by
Petra Hirsova, Mayo Clinic College of Medicine

The Contribution of Dietary Fructose to Non-alcoholic Fatty Liver Disease.
TNF plays a crucial role in inflammation by signaling via T cell TNFR2.
Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells.
Toward a Paradigm to Distinguish Distinct Functions of FOXP3+ Regulatory T Cells.
Targeting T Cell Subtypes for NAFLD and NAFLD-Related HCC Treatment: An Opinion.
Lipidized Prolactin-Releasing Peptide as a New Potential Tool to Treat Obesity and Type 2 Diabetes Mellitus: Preclinical Studies in Rodent Models.
Cellular heterogeneity of circulating CD4+CD8+ double-positive T cells characterized by single-cell RNA sequencing.
Spatial determinates of effector and memory CD8+ T cell fates.

Front Pharmacol. 2021 ;12 783393

The Contribution of Dietary Fructose to Non-alcoholic Fatty Liver Disease.

Siyu Yu, Chunlin Li, Guang Ji, Li Zhang.

  Fructose, especially industrial fructose (sucrose and high fructose corn syrup) is commonly used in all kinds of beverages and processed foods. Liver is the primary organ for fructose metabolism, recent studies suggest that excessive fructose intake is a driving force in non-alcoholic fatty liver disease (NAFLD). Dietary fructose metabolism begins at the intestine, along with its metabolites, may influence gut barrier and microbiota community, and contribute to increased nutrient absorption and lipogenic substrates overflow to the liver. Overwhelming fructose and the gut microbiota-derived fructose metabolites (e.g., acetate, butyric acid, butyrate and propionate) trigger the de novo lipogenesis in the liver, and result in lipid accumulation and hepatic steatosis. Fructose also reprograms the metabolic phenotype of liver cells (hepatocytes, macrophages, NK cells, etc.), and induces the occurrence of inflammation in the liver. Besides, there is endogenous fructose production that expands the fructose pool. Considering the close association of fructose metabolism and NAFLD, the drug development that focuses on blocking the absorption and metabolism of fructose might be promising strategies for NAFLD. Here we provide a systematic discussion of the underlying mechanisms of dietary fructose in contributing to the development and progression of NAFLD, and suggest the possible targets to prevent the pathogenetic process.

Keywords:  de novo lipogenesis; fructose; inflammation; intestinal environment; non-alcoholic fatty liver disease (NAFLD)

DOI:  https://doi.org/10.3389/fphar.2021.783393
Proc Natl Acad Sci U S A. 2021 Dec 14. pii: e2109972118. [Epub ahead of print]118(50):

TNF plays a crucial role in inflammation by signaling via T cell TNFR2.

Muhammad S Alam, Shizuka Otsuka, Nathan Wong, Aamna Abbasi, Matthias M Gaida, Yu Fan, Daoud Meerzaman, Jonathan D Ashwell.

  TNF, produced largely by T and innate immune cells, is potently proinflammatory, as are cytokines such as IFN-γ and IL-17 produced by Th1 and Th17 cells, respectively. Here, we asked if TNF is upstream of Th skewing toward inflammatory phenotypes. Exposure of mouse CD4+ T cells to TNF and TGF-β generated Th17 cells that express low levels of IL-17 (ROR-γt+IL-17lo) and high levels of inflammatory markers independently of IL-6 and STAT3. This was mediated by the nondeath TNF receptor TNFR2, which also contributed to the generation of inflammatory Th1 cells. Single-cell RNA sequencing of central nervous system-infiltrating CD4+ T cells in mouse experimental autoimmune encephalomyelitis (EAE) found an inflammatory gene expression profile similar to cerebrospinal fluid-infiltrating CD4+ T cells from patients with multiple sclerosis. Notably, TNFR2-deficient CD4+ T cells produced fewer inflammatory mediators and were less pathogenic in EAE and colitis. IL-1β, a Th17-skewing cytokine, induced TNF and proinflammatory granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, which was inhibited by disruption of TNFR2 signaling, demonstrating IL-1β can function indirectly via the production of TNF. Thus, TNF is not just an effector but also an initiator of inflammatory Th differentiation.

Keywords:  GM-CSF; TNFR2; Th skewing; inflammatory disease

DOI:  https://doi.org/10.1073/pnas.2109972118
Immunity. 2021 Nov 30. pii: S1074-7613(21)00496-9. [Epub ahead of print]

Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells.

Eunha Kim, Donggi Paik, Ricardo N Ramirez, Delaney G Biggs, Youngjun Park, Ho-Keun Kwon, Gloria B Choi, Jun R Huh.

  Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.

Keywords:  Citrobacter; autism spectrum disorder; colitis; gut microbiota; inflammatory bowel diseases; interleukin-17A; maternal immune activation; neurodevelopmental disorders; pregnancy

DOI:  https://doi.org/10.1016/j.immuni.2021.11.005
Immunohorizons. 2021 Dec 10. 5(12): 944-952

Toward a Paradigm to Distinguish Distinct Functions of FOXP3+ Regulatory T Cells.

Samuel E Weinberg, Benjamin D Singer.

FOXP3+ regulatory T (Treg) cells are a unique subset of CD4+ T cells that classically function as master regulators of immune homeostasis. Besides this canonical suppressive role, which is required to maintain self-tolerance, a growing body of literature has identified Treg cells as critical orchestrators of tissue protection during acute stress and as effector cells that drive repair following tissue injury. Despite substantial interest in these distinct roles, the field has struggled to disentangle Treg cell suppressive functions from those that promote tissue defense and repair. In this article, we will examine the literature in the context of specific physiologic settings, contrasting the suppressive function of Treg cells with their emerging roles in promoting tissue homeostasis and tissue repair. Further, we will discuss a new paradigm differentiating tissue defense from tissue repair-a paradigm needed to translate Treg cell-based therapies to the clinic.

DOI: https://doi.org/10.4049/immunohorizons.2100046
Front Med (Lausanne). 2021 ;8 789859

Targeting T Cell Subtypes for NAFLD and NAFLD-Related HCC Treatment: An Opinion.

Chunye Zhang, Ming Yang.



Keywords:  HCC; NAFLD; T cell subpopulation; chemokines; cytokines; treatment

DOI:  https://doi.org/10.3389/fmed.2021.789859
Front Pharmacol. 2021 ;12 779962

Lipidized Prolactin-Releasing Peptide as a New Potential Tool to Treat Obesity and Type 2 Diabetes Mellitus: Preclinical Studies in Rodent Models.

Lucia Mráziková, Barbora Neprašová, Anna Mengr, Andrea Popelová, Veronika Strnadová, Lucie Holá, Blanka Železná, Jaroslav Kuneš, Lenka Maletínská.

  Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

Keywords:  leptin resistance; obesity; prolactin-releasing peptide; rodent models; type 2 diabetes

DOI:  https://doi.org/10.3389/fphar.2021.779962
Sci Rep. 2021 Dec 08. 11(1): 23607

Cellular heterogeneity of circulating CD4+CD8+ double-positive T cells characterized by single-cell RNA sequencing.

Sung Min Choi, Hi Jung Park, Eun A Choi, Kyeong Cheon Jung, Jae Il Lee.

Circulating CD4+CD8+ double-positive (DP) T cells are associated with a variety of disease states. However, unlike conventional T cells, the composition of this population is poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to analyze the composition and characteristics of the DP T cell population circulating in the peripheral blood of cynomolgus monkeys. We found that circulating DP T cells not only contain a large number of naïve cells, but also comprise a heterogeneous population (CD4 CTL-, Eomes+ Tr1-, Th2-, Th17-, Tfh-, Treg-, CD8 CTL-, and innate-like cells) with multiple potential functions. Flow cytometry analysis revealed that a substantial number of the naïve DP T cells expressed CD8αβ, as well as CD8αα, along with high expression of CD31. Moreover, the CD4hiCD8lo and CD4hiCD8hi populations, which express high levels of the CD4 coreceptor, comprised subsets characterized by helper and regulatory functions, some of which also exhibited cytotoxic functions. By contrast, the CD4loCD8hi population with high CD8 coreceptor expression comprised a subset characterized by CD8 CTL- and innate-like properties. Taken together, the data show that scRNA-seq analysis identified a more diverse subset of the circulating DP cells than is currently known, despite this population being very small.

DOI: https://doi.org/10.1038/s41598-021-03013-4
Immunol Rev. 2021 Dec 09.

Spatial determinates of effector and memory CD8+ T cell fates.

Brigette C Duckworth, Raymond Z Qin, Joanna R Groom.

  The lymph node plays a critical role in mounting an adaptive immune response to infection, clearance of foreign pathogens, and cancer immunosurveillance. Within this complex structure, intranodal migration is vital for CD8+ T cell activation and differentiation. Combining tissue clearing and volumetric light sheet fluorescent microscopy of intact lymph nodes has allowed us to explore the spatial regulation of T cell fates. This has determined that short-lived effector (TSLEC ) are imprinted in peripheral lymph node interfollicular regions, due to CXCR3 migration. In contrast, stem-like memory cell (TSCM ) differentiation is determined in the T cell paracortex. Here, we detail the inflammatory and chemokine regulators of spatially restricted T cell differentiation, with a focus on how to promote TSCM . We propose a default pathway for TSCM differentiation due to CCR7-directed segregation of precursors away from the inflammatory effector niche. Although volumetric imaging has revealed the consequences of intranodal migration, we still lack knowledge of how this is orchestrated within a complex chemokine environment. Toward this goal, we highlight the potential of combining microfluidic chambers with pre-determined complexity and subcellular resolution microscopy.

Keywords:  T cells; cell differentiation; cell trafficking; chemokines; ex vivo imaging; lymph nodes

DOI:  https://doi.org/10.1111/imr.13044